Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Nucl Med. 2013 Mar;54(3):388-96. doi: 10.2967/jnumed.112.107995. Epub 2013 Feb 12.
Identification of safe and valid PET radioligands for metabotropic glutamate receptor, type 5 (mGluR5), is essential to measure changes in brain mGluR5 in neuropsychiatric disorders, to confirm central mGluR5 occupancy of drug candidates, and to guide dose selection for obtaining an optimum therapeutic window. Here we present the results of a first-in-human study assessing the safety and effectiveness of a novel PET radiopharmaceutical, (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB), for quantifying regional brain concentrations of mGluR5.
Quantification of whole-body biokinetics was conducted in 6 healthy adults (3 men and 3 women). The radiation safety profile was estimated with OLINDA/EXM software. Subsequently, pairs of dynamic brain scans were obtained for 11 healthy men to identify optimal methods for derivation of regional distribution volume and binding potential and to determine the repeatability of measurement.
The whole-body effective radiation dose was approximately 17 μSv/MBq (62 mrem/mCi), with the gallbladder receiving the highest dose of 190 μSv/MBq. In brain studies, time-activity curves showed high accumulation in the insula/caudate nucleus, moderate uptake in the thalamus, and the lowest concentration in the cerebellum/pons. The plasma reference graphical analysis method appeared optimal for (18)F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼0.5 in the globus pallidus to ∼3.5 in the insula) for target regions. Safety assessments revealed no clinically meaningful changes in vital signs, electrocardiogram, or laboratory values.
(18)F-FPEB is safe and well tolerated, and its regional cerebral distribution is consistent with previous reports in the literature for metabotropic glutamate receptors. The repeatability of measurement suggests that (18)F-FPEB is suitable for quantifying mGluR5 in humans.
鉴定代谢型谷氨酸受体 5（mGluR5）的安全有效的正电子发射断层扫描（PET）放射性配体，对于测量神经精神疾病中脑内 mGluR5 的变化、确认候选药物对中枢 mGluR5 的占据以及指导获得最佳治疗窗的剂量选择至关重要。本文介绍了一项首例人体研究的结果，该研究评估了一种新型 PET 放射性药物，即（18）F-3-氟-5-[(吡啶-3-基)乙炔基]苯甲腈（（18）F-FPEB），用于定量测量 mGluR5 的脑内浓度的安全性和有效性。
在 6 名健康成年人（3 名男性和 3 名女性）中进行了全身生物动力学的定量。使用 OLINDA/EXM 软件估计辐射安全性概况。随后，对 11 名健康男性进行了一对动态脑扫描，以确定衍生局部分布容积和结合潜能的最佳方法，并确定测量的重复性。
全身有效辐射剂量约为 17 μSv/MBq（62 mrem/mCi），胆囊接受的剂量最高，为 190 μSv/MBq。在脑部研究中，时间-活性曲线显示在脑岛/尾状核中高度聚集，在丘脑中有中等摄取，而在小脑/脑桥中浓度最低。血浆参考图分析方法似乎是（18）F-FPEB 的最佳方法；它显示出可接受的无置换结合潜能的测试-重测变异性（<10%），并确定了目标区域的最高无置换结合潜能值（从纹状体中的约 0.5 到脑岛中的约 3.5）。安全性评估显示生命体征、心电图或实验室值没有出现有临床意义的变化。
（18）F-FPEB 安全且耐受良好，其脑内分布与文献中先前关于代谢型谷氨酸受体的报道一致。测量的可重复性表明（18）F-FPEB 适合用于人类 mGluR5 的定量。
